This is a request for a Mentored Research Scientist Development Award (K01) for advanced training in research on the neurochemical underpinnings of tobacco smoking and the influence of sex and sex hormones using neuroreceptor-imaging technologies. Sex differences exist in a variety of behaviors related to tobacco smoking such as craving, sensitivity to cues, and treatment effects;however, the mechanisms underlying these differences are unclear. Understanding the neurochemistry mediating sex differences in tobacco smoking will lead to the development of much needed sex-specific treatments for smoking cessation. The primary focus of the proposed studies is training in neuroreceptor imaging using single photon emission computed tomography (SPECT) and positron emission tomography (PET) modalities to determine the influence of sex, sex hormones and tobacco smoking on nicotinic acetylcholine receptor (nAChR) expression. We propose to determine whether there are sex differences in agonist binding to the |32-nAChR by imaging healthy men and women nonsmokers, and healthy men and women smokers with women in different phases of the menstrual cycle using the p2-nAChR agonist radiotracer [123I]5-IA-85380 and SPECT. The training component includes supervised research, formal coursework in SPECT and PET theory and methodology, and advanced training in statistical parametric mapping. The multidisciplinary nature of this project, conducted under the mentorship of Drs. Julie Staley, Stephanie O'Malley, and Rich Carson, in collaboration with faculty specializing in SPECT and PET image analysis, pharmacokinetic modeling, radiochemistry, tobacco smoking, and clinical psychopharmacology will provide a valuable opportunity for the candidate to address issues regarding the effects of sex and hormones on nAChR expression in living humans. The project will enable the candidate to develop into an independent investigator in the application of imaging modalities to the investigation of the neurochemical mechanisms underlying substance disorders. The ultimate goal of these studies is to investigate differences in the brains of men and women tobacco smokers, which will provide information on why women often have a harder time quitting smoking than men. This will aid in the development of medications that are specifically designed to help both women and men quit smoking.